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Brain Cell Overgrowth Before Birth Associated With Autism Severity

A puzzle that spells the word autism.
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Brain organoids, sometimes nicknamed “mini-brains”, enable scientists to explore the function of neurons in healthy and diseased states outside of the human brain.

Derived from stem cells, brain organoids can be coaxed to develop complex neural networks that mimic different stages of human development, including the formation of the nervous system in utero.

Scientists at the University of California San Diego (UCSD) are the first to create brain cortical organoids (BCOs) from young children with idiopathic autism spectrum disorder (ASD) – a type of ASD that lacks a clear cause – and study them while observing the child’s development.

This novel approach enabled lead author Professor Alysson R. Muotri and colleagues to explore whether a biological mechanism underpins varying levels of severity in ASD symptoms. Their research is published in Molecular Autism.

“Autism is a very heterogenous condition. You can have individuals that are quite independent and live an almost normal life,” Muotri, who is a professor in the Departments of Pediatrics and Cellular & Molecular Medicine at UCSD, told Technology Networks. “On the other hand, there are individuals with profound autism, sometimes also referred to level three, which require substantial support for living. The reasons why there are such a spectrum is unknown.”

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Muotri and colleagues created 4910 embryonic-stage BCOs modeling the fetal cortex from 10 toddlers with ASD and 6 neurotypical controls. The cortex is a gray matter-rich area of the brain that is involved in a wide variety of functions, including learning, memory, consciousness, the generation of emotions and sensory processing.

“Previous work on ASD-derived iPSC-models always relays in a small number of subjects, thus, with low statistical power. Our analyses used hundreds of subjects and thousands of brain organoids, making the data very robust,” Muotri said.

“We used a protocol that was created in 2019, where organoids have very sophisticated neural networks that mimic EEGs [electroencephalograms] from the developing human brain,” he continued.

The team’s method is now published in Nature Protocols.

Bigger neurons correlate with increased ASD symptom severity

The size and growth rate of the BCOs, levels of neurogenesis markers and, at the molecular level, the activity and expression of an enzyme known as NDEL1, were analyzed. The results were studied in conjunction with other data sets obtained from the toddlers, including neuroimaging and social and language symptoms data.

Brain organoids derived from ASD toddlers were on average 40% larger than those from neurotypical toddlers. At the cellular and molecular level, these BCOs also demonstrated higher levels of neurogenesis and downregulated NDEL1 activity.

Muotri and colleagues found that the larger the toddler’s BCOs, the greater the severity of their social symptoms. While this data cannot prove causation, it suggests that subtypes of ASD could develop in utero.

“Our work with BCOs revealed that embryonic trajectories of neurodevelopment are predictive of how severe the type of autism is. Because BCOs capture the genetic background of the individual, we can say that these differences are genetically encoded,” Muotri told Technology Networks.

The researchers have formulated several hypotheses on why this correlation may exist: “First, we found that the NDEL1 enzyme, responsible for embryo size, is misregulated in BCOs from ASD children: the greater the reduction in NDEL1 expression, the more overly enlarged the BCO was,” Muotri said. “While this is an interesting correlation, we need to causally demonstrate that this enzyme is indeed regulating the number of neurons in the brain. Then, we need to figure out why this enzyme is misregulated in ASD.”

This study is “one of a kind” the researchers said, because it utilizes patient-derived brain organoids to make correlations with human behavior. These insights could not be obtained from current non-invasive technologies, Muotri emphasized: “The only way to validate that ASD subjects have more neurons with current technology is to look at postmortem brain tissue, which has been done to some extent by Dr. Eric Courchesne.” Courchesne, a professor in Neuroscience at UCSD, is the study’s first author.

“However, postmortem tissues are also limited,” Muotri continued. “We need non-invasive technologies, with high resolution, which could be used to measure brain growth and number of neurons in utero.”

The UCSD team will now focus its efforts on understanding the molecular and cellular mechanisms underlying the different trajectories in ASD-derived BCOs.

Muotri hopes that this pursuit will reveal novel, more effective therapeutic opportunities for autistic individuals who are more vulnerable: “Because autism is so variable, it could be that profound autism and high-functioning autism are two different conditions with some clinical overlap. This concept will be important to design better treatments that attend to each subtype of autism in a better way. The goals and desires of these two groups are not always the same,” he concluded.

Dr. Alysson R. Muotri was speaking to Molly Campbell, Senior Science Writer for Technology Networks.

Reference: Courchesne E, Taluja V, Nazari S, et al. Embryonic origin of two ASD subtypes of social symptom severity: the larger the brain cortical organoid size, the more severe the social symptoms. Mol Autism. 2024;15(1):22. doi:10.1186/s13229-024-00602-8

About the interviewee:

Dr. Alysson R. Muotri is a professor at the Departments of Pediatrics and Cellular & Molecular Medicine at UC San Diego. He is also the director of the Sanford Stem Cell Education and Integrated Space Stem Cell Orbital Research (ISSCOR), the director of the Archealization Center (ArchC) and associate director for the Center for Academic Research & Training in Antropogeny (CARTA).

Muotri earned a BSc in Biological Sciences from the State University of Campinas in 1995 and a PhD in Genetics in 2001 from the University of Sao Paulo, Brazil. He joined the Salk Institute as Pew Latin America Fellow in 2002 for postdoctoral training in the fields of neuroscience and stem cell biology. His research focuses on brain evolution and modeling neurological diseases using human-induced pluripotent stem cells and brain organoids. He has received several awards, including the prestigious NIH Director’s New Innovator Award, NARSAD, Emerald Foundation Young Investigator Award, Surugadai Award, Rock Star of Innovation, NIH EUREKA Award and two Telly Awards for Excellence in Science Communication, among several others.